CN107033043A - N- replaces benzenesulfonyl-substituted benzene formyl amine compound and its prepares the purposes of medicine - Google Patents

N- replaces benzenesulfonyl-substituted benzene formyl amine compound and its prepares the purposes of medicine Download PDF

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CN107033043A
CN107033043A CN201610080438.4A CN201610080438A CN107033043A CN 107033043 A CN107033043 A CN 107033043A CN 201610080438 A CN201610080438 A CN 201610080438A CN 107033043 A CN107033043 A CN 107033043A
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benzenesulfonyl
group
nitros
amino
benzamide
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CN107033043B (en
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郑灿辉
朱驹
周有骏
王明萍
杨超
田巍
刘昱
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Second Military Medical University SMMU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/24—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/25—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/51—Y being a hydrogen or a carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a class N replace benzenesulfonyl substituted benzamide class compound, its crystal formation, pharmaceutically acceptable salt class, hydrate, solvate or prodrug, and preparation method thereof and pharmaceutical applications.Shown in the general structure of the compound such as formula (I).Experiment shows itself and Bcl 2, Bcl xLThere is preferable binding ability with the albumen of Mcl 1, preferable broad-spectrum anti-tumor activity is shown to human blood tumour (leukaemia, myeloma) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer).Therefore these compounds have the medicine for preparing the disease related with the high expression of the protein family anti-apoptotic members of Bcl 2, prepare antineoplastic, and prepare synergist and other antineoplastics or radiotherapy shares to treat the potential use of tumour.

Description

N- replaces benzenesulfonyl-substituted benzene formyl amine compound and its prepares medicine Purposes
Technical field
The present invention relates to pharmaceutical technology field, more particularly it relates to which a class N- replaces benzenesulfonyl-substituted benzene Carbox amide, further relates to the composition of such compound, preparation method and its is preparing treatment and Bcl-2 protein families Purposes in medicine, antineoplastic and the synergist of the related disease of anti-apoptotic members height expression or symptom.
Background technology
Apoptosis is cell by the programmed cell death carried out after certain signal stimulus, is a kind of substantially biological of cell Learn phenomenon.Bcl-2 protein families play important adjustment effect in Apoptosis path.It can be divided into anti-apoptotic members (such as Bcl-2, Bcl-xL, Mcl-1 etc.) and promote the class of apoptotic members two.Research shows Bcl-2 protein family anti-apoptotic members Overexpression can cause normal apoptosis path to be obstructed, the generation with many diseases (such as tumour, autoimmune disease) Correlation, particularly tumour produce and occurred one of the major reason of resistance (Nature 2000,407,796-801；Nat Rev Cancer 2004,4,592-603.)。
Research show that Bcl-2 protein families anti-apoptotic members are over-expressed in many tumours, different tumours with And expression difference (the Oncogene 2003,22,8590-607 in different tumors subtypes；Oncogene 2008,27, 6398-406).By the Anti-G value for the anti-apoptotic members for suppressing to over-express in tumour cell, it can recovered just Normal apoptosis pathway, increases its sensitiveness to chemotherapy radiotherapy, is the new strategy for treating tumour.Bcl-2 protein family anti-cells Apoptosis member is to be combined by the hydrophobic groove on its surface with promoting the Bcl-2 protein family conservative regions BH3 of apoptotic members And interact, to adjust the normal Apoptosis of cell.Micromolecular inhibitor is by being incorporated into anti-apoptotic members Surface hydrophobicity groove, can disturb rush apoptotic members BH3 regions are in combination to play a part of promoting Apoptosis (Nat Rev Cancer 2005,5,876-85；Kelly,P.N.；Cell Death Differ 2011,18,1414-24.).It is near Year, the type small molecular inhibitor caused the broad interest of researcher, and a series of little molecules in inhibiting are found that by different approaches Agent, wherein having four (ABT-199, ABT-263, AT-101, GX15-07) as oral antineoplastic enters clinical research. Result of study shows that Bcl-2 protein family anti-apoptotic members micromolecular inhibitors show preferable antitumor action and right The synergy synergy of other antineoplastics or radiotherapy, with good development prospect (Nat Rev Drug Discov 2008,7,989-100；Chinese Journal of New Drugs 2008,17,2008-2013；Pharmacy progress 2004,28,97-103；Clin Cancer Res 2012,18,1-7；J Thorac Oncol 2011,6,1757-1760；Lung Cancer 2011,74, 481-485)。
In summary, the inhibitor of Bcl-2 protein family anti-apoptotic members is researched and developed, for the treatment of the diseases such as tumour It is significant.
The content of the invention
The invention aims to provide the new N- substitution benzenesulfonyl-substituted benzene formyl amine compounds of a class and be somebody's turn to do Preparation method, purposes and the composition of class compound.
Replace benzenesulfonyl-substituted benzene formyl amine compound there is provided a class N- in the first aspect of the present invention, it is tied Shown in structure formula such as formula (I)：
In formula,
R1Group is-ZR5(II), wherein, Z is
R5It is hydrogen atom, unsubstituted or substituted aromatic monocyclic, unsubstituted or substituted hydrogenated aromatic condensed ring is unsubstituted or substituted Aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Straight chain, side chain or cyclic alkane base, halogen；
Or R5Group is-YR6(III), wherein, Y is C1~C7Straight chain, side chain or cyclic alkane base, C1~C7Straight chain, side chain Or cyclic olefin base, R5It is hydrogen atom, unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted or polysubstituted, is halogen Element, unsubstituted or halo C1~C5Straight chain, side chain or cyclic alkane base, C1~C5Alkoxy grp, nitro, trifluoromethyl, cyano group, Sulfonic group, carboxyl；
Or R5Group is-YR6(III), wherein, Y is unsubstituted or substituted aromatic monocyclic, and substituent is monosubstituted or taken more Generation, R6Group is VR10(VII), wherein, V isFor not Substitution or substituted aroma condensed ring, substituent is monosubstituted or polysubstituted, is C1~C5Straight chain, side chain or cyclic alkane base, halogen,
R2The position of substitution is located at two or three-digit, is hydrogen atom, hydroxyl, amino, halogen, C1~C5Straight chain, side chain or ring-type alkane Alkyl；
Or R2Group is-XR7(IV), wherein, X is O, N, S,R7It is hydrogen atom, aromatic monocyclic, Aromatic condensed ring, C1~C7Straight chain, side chain or cyclic alkane base,
R3Group is hydrogen atom, halogen, amino, hydroxyl, C1~C5Straight chain, side chain or cyclic alkane base；
Or R3Group is-NWR8(V), wherein, W is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, branch Chain or cyclic olefin base, R8It is hydrogen atom, sulfonic group, carboxyl, nitro, trifluoromethyl, cyano group；
Or R8Group is-UR9(VI), U is S, O, N,R7It is hydrogen atom, aromatic monocyclic, fragrance is thick Ring, C1~C7Straight chain, side chain or cyclic alkane base,
R4The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano group, sulfonic group, carboxyl, C1~C5 Straight or branched alkyl, halogen, hydroxyl, amino.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), its In, Y is C1~C7Straight chain, side chain or cyclic alkane base, C1~C7 straight chains, side chain or cyclic olefin base, R6It is unsubstituted or substituted Aromatic monocyclic, wherein, substituent is monosubstituted, is halogen, unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoro Methyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), its In, Y is C1~C7Linear paraffin base, C1~C7Linear alkene base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is It is monosubstituted, it is halogen, unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), Wherein, Y is C1~C7Linear paraffin base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted, is halogen, Unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y is C1~C7Linear paraffin Base, R6It is aromatic monocyclic,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is-UR9(VI), U is S, O, N, R9 It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y is C1~C7Linear paraffin Base, R6It is aromatic monocyclic,
R2For hydrogen atom,
R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is-UR9(VI), U is S, O, N, R9 It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y is C1~C4Linear paraffin Base, R6It is aromatic monocyclic,
R2For hydrogen atom,
R3Group is-NWR8(V), wherein, W is C1~C4Linear paraffin base, R8Group is-UR9(VI), U is S, R9It is virtue It is fragrant monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), Wherein, Y is C1~C7Linear alkene base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted, is halogen, Unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y is C1~C7Linear alkene Base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted, is halogen, unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y is C1~C4Linear alkene Base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted, is halogen, unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), wherein, Z isR5 It is unsubstituted or substituted aromatic monocyclic, unsubstituted or substituted aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1 ~C5Straight chain, side chain or cyclic alkane base,
R2For hydrogen atom,
R3Group is hydrogen atom；
Or R3Group is-NWR8(V), wherein, W is C1~C10Straight chain, side chain or cyclic alkane base, R8Group is-UR9 (VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), wherein, Z isR5 It is unsubstituted aromatic monocyclic, unsubstituted or substituted aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Straight chain Alkyl,
R2For hydrogen atom,
R3Group is hydrogen atom；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), wherein, Z isR5It is unsubstituted aromatic monocyclic, it is unsubstituted or take For aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Linear paraffin base,
R2For hydrogen atom,
R3Group is hydrogen atom；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is-UR9(VI), U is S, R9It is Aromatic monocyclic,
R4For hydrogen atom, nitro.
It is used as the preference of the present invention：
R1Group is-ZR5(II), wherein, Z isR5It is unsubstituted aromatic monocyclic, it is unsubstituted or take For aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Linear paraffin base,
R2For hydrogen atom,
R3Group is hydrogen atom；
Or R3Group is-NWR8(V), wherein, W is C1~C4Linear paraffin base, R8Group is-UR9(VI), U is S, R9It is Aromatic monocyclic,
R4For hydrogen atom, nitro.
As a kind of preferred embodiment of the present invention, described compound is any one in following compounds：
1) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (2- phenylacetyl groups amino) benzamide
2) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- hydrocinnamoyls amino) benzamide
3) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (phenyl) Acryloyl amino) benzene Formamide
4) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- chlorphenyls) acryloyl group ammonia Base) benzamide
5) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- chlorphenyls) acryloyl group ammonia Base) benzamide
6) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- chlorphenyls) acryloyl group ammonia Base) benzamide
7) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- methoxyphenyls) acryloyl groups Amino) benzamide
8) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- methoxyphenyls) acryloyl groups Amino) benzamide
9) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- methoxyphenyls) acryloyl groups Amino) benzamide
10) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- trifluoromethyls) propylene Acyl amino) benzamide
11) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- trifluoromethyls) propylene Acyl amino) benzamide
12) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- trifluoromethyls) propylene Acyl amino) benzamide
13) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- aminomethyl phenyls) acryloyl groups Amino) benzamide
14) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- aminomethyl phenyls) acryloyl groups Amino) benzamide
15) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- aminomethyl phenyls) acryloyl groups Amino) benzamide
16) 2- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) acetic acid
17) 3- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) propionic acid
18) 4- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) butyric acid
19) 5- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) valeric acid
20) 6- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) caproic acid
21) 7- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) enanthic acid
22) 8- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia Sulfonyl) phenyl amino) octanoic acid
23) N- (3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
24) N- (the fluoro- 3- nitrobenzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzene Formamide
25) N- (the fluoro- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
26) N- (the chloro- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
27) N- (the bromo- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
28) N- (benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
29) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (4- (1- (3,5,5,8,8- pentamethyls - 5,6,7,8- naphthane -2- bases) vinyl) benzoyl-amido) benzamide
30) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (1- (3,5,5,8,8- pentamethyl -5, 6,7,8- naphthane -2- bases) vinyl) benzamide
31) N- (3- nitrobenzenesulfonyls) -4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) ethene Base) benzamide
32) N- (benzenesulfonyl) -4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) benzene Formamide
33) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3,5,5,8,8- pentamethyl -5,6,7, 8- naphthane -2- carbonyls) benzamide
34) N- (3- nitrobenzenesulfonyls) -4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzene first Acid amides
35) N- (benzenesulfonyl) -4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzamide
36) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (benzoyl) benzamide.
Replace benzenesulfonyl-substituted benzene formyl amine chemical combination there is provided the N- described in formula (I) in the second aspect of the present invention The crystal formation of thing, pharmaceutically acceptable inorganic acid salt or acylate, hydrate, solvate or prodrug.
In the third aspect of the present invention there is provided a kind of pharmaceutical composition, described pharmaceutical composition, which contains, pharmaceutically may be used The excipient or carrier of receiving, and N- substitution benzenesulfonyl-substituted benzene formyl amine compounds or formula (I) described in formula (I) Described N- replaces crystal formation, the pharmaceutically acceptable inorganic acid salt or organic of benzenesulfonyl-substituted benzene formyl amine compound Hydrochlorate, hydrate, solvate or prodrug..
Replace benzenesulfonyl-substituted benzene formyl amine chemical combination there is provided the N- described in formula (I) in the fourth aspect of the present invention Thing, or N- substitution benzenesulfonyl-substituted benzene formyl amine compounds described in formula (I) crystal formation, pharmaceutically acceptable inorganic The purposes of hydrochlorate or acylate, hydrate, solvate or prodrug in medicine is prepared, described medicine is used for：
A) treatment and Bcl-2, Bcl-xLThe disease or symptom related to Mcl-1 activity；
B) it is antitumor；Or
C) as antineoplastic or the synergist of radiotherapy.
As a kind of embodiment of the present invention, described tumour is leukaemia, myeloma, oophoroma, breast cancer, Melanoma, lung cancer.
Replace benzenesulfonyl-substituted benzene formyl amine chemical combination there is provided the N- described in formula (I) in the fifth aspect of the present invention The preparation method of thing comprises the following steps：
Intermediate (VIII) and 2- or 3- substitution -4- substituted benzenes sulfanilamide (SN) (Ⅸ), generate target chemical combination under the conditions of condensation reaction Thing (I)；
Wherein, intermediate (VIII) structural formula is：
2- or 3- substitutions -4- substituted benzenes sulfanilamide (SN) (Ⅸ) structural formula is：
If desired, gained formula (I) compound in above-mentioned steps is formed to the pharmaceutical salts of formula (I) compound with medicinal basic, or Gained formula (I) compound in above-mentioned steps is obtained to the pure optical isomer of formula (I) compound by spatial chemistry separation method.
In another preference, the condensation reaction condition used in the synthesis of described compound (1) for add 1- ethyls- 3- (3- dimethylamine propyls) carbodiimide hydrochloride (EDCI).
In a preference, the condensation reaction condition used in the synthesis of described target compound (I) is adds 1,3- Dicyclohexylcarbodiimide (DCC).
In another preference, the condensation reaction condition used in the synthesis of described target compound (I) is adds 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU).
In another preference, the condensation reaction condition used in the synthesis of described target compound (I) is first in Thionyl chloride is added in mesosome (VIII) acyl chlorides is made, add 2- or 3- substitution -4- substituted benzenes sulfanilamide (SN) (Ⅸ).
In another preference, spatial chemistry separation method in the synthesis of described target compound (I) for fractionation, again Crystallization, introduction single chiral source or Chromatographic resolution.
Herein, " prodrug " refers to that a reagent is converted into prototype medicine in vivo.Prodrug is typically useful, because at certain In the case of kind, they may administration easier than prototype medicine.Prodrug is typically the precursor of medicine, and ensuing administration and absorption are converted For active material, or by some processes it is changed into the stronger species of activity, is such as converted by metabolic pathway.What some prodrugs had Chemical group makes its activity relatively low and/or the dissolubility or some other properties of contrast prototype medicine are changed.Once prodrug Chemical group is removed and/or it is modified, and obtains active drug.
Described pharmaceutically acceptable inorganic acid salt may be selected from hydrochloride, sulfate, phosphate, diphosphate, hydrogen bromine Hydrochlorate, nitrate；Described pharmaceutically acceptable acylate may be selected from acetate, maleate, fumarate, tartaric acid Salt, succinate, lactate, tosilate, salicylate, oxalates.
Pharmaceutical composition of the present invention, can be solid form or liquid form, and described pharmaceutical dosage form can be with It is tablet, capsule, powder agent, granule, supensoid agent or injection., can be with one when the compounds of this invention is used for such use Plant or a variety of pharmaceutically acceptable carriers or excipient mixing, such as solvent, diluent, and can be oral with following form Administration：Tablet, pill, capsule, dispersible powder, particle or suspension (containing such as from about 0.05-5% suspending agents), syrup (contain Have such as from about 10-50% sugar) and elixir (containing about 20-50% ethanol), or be administered in external application mode：Ointment, gel, pastille Adhesive plaster etc., or carried out with sterile injectable solution or form of suspension (containing about 0.05-5% suspending agents in isotonic medium) Parenteral routes.For example, these pharmaceutical preparations can contain the about 0.01-99%, more preferably about 0.1%- mixed with carrier The active component of 90% (weight).
" pharmaceutically acceptable carrier " is referred to：One or more biocompatible solids or liquid filler or gelatinous mass, They are adapted to people and used and it is necessary to have enough purity and sufficiently low toxicity." compatibility " herein means during generation is composition Each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the curative effect of compound.Pharmaceutically Acceptable carrier part example has sugared (such as glucose, sucrose, lactose), starch (such as cornstarch, farina), Cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, cellulose ethanoate), gelatin, talcum powder, Gu Body lubricant (such as odium stearate, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame oil, peanut oil, olive oil) is more First alcohol (such as propane diols, glycerine, mannitol, sorbierite), emulsifying agent (such as Tweens), wetting agent (such as dodecyl sodium sulfonate Sodium), colouring agent, flavor enhancement, stabilizer, antioxidant, preservative, apirogen water etc..
Described " synergist " refers to a class with certain class compatibility of drugs and lived in use, strengthening such medicine with specific mechanism Property medicine, play synergy., can be with other drugs drug combination as synergist, " administering drug combinations " refer to will be several Medicine selected by kind gives patient's medication, with identical or different administering mode in identical or different time administration. Term " collaboration ", " synergy " or " synergy ", as used herein, refers to and there is suppression Bcl-2, Bcl-x to scriptLOr Mcl-1 Activity, or anti-tumor drug can strengthen original Drug inhibition Bcl-2, Bcl-x when sharing another medicineLOr Mcl-1 Activity, or antitumous effect effect.
The invention has the advantages that：
1st, N- of the invention substitution benzenesulfonyl-substituted benzene formyl amine compound is shown and Bcl-2, Bcl-xLWith The preferable binding ability of Mcl-1 albumen, particularly part of compounds Mcl-1 albumen show more preferable binding ability.Therefore this A little compounds have the medicine for preparing the disease related to the high expression of Bcl-2 protein families anti-apoptotic members, prepare Antineoplastic, and prepare synergist and other antineoplastics or radiotherapy shares to treat the potential use of tumour.
2nd, N- of the invention replaces benzenesulfonyl-substituted benzene formyl amine compound to human blood tumour (leukaemia, marrow Knurl) and solid tumor (oophoroma, breast cancer, melanoma, lung cancer) show preferable broad-spectrum anti-tumor activity.Therefore, this hair Bright compound is expected have good DEVELOPMENT PROSPECT.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) It can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.As space is limited, exist This no longer tires out one by one states.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part, or according to the condition proposed by manufacturer.Unless otherwise indicated, otherwise percentage and number are percentage by weight and weight Number.
Embodiment 1
N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl -4- (3- hydrocinnamoyls amino) benzamide (tables 1 Middle compound 2) preparation：
Synthetic route is：
1st, the preparation of hydrocinnamamide yl benzoic acid ethyl ester
Benzenpropanoic acid 0.305g (2mmol), ethylaminobenzoate 0.348g (2mmol), 1- ethyls -3- (3- diformazan ammonia Propyl group) carbodiimide hydrochloride (EDCI) 0.775g (4mmol), DMAP 0.049g (0.4mmol), with anhydrous DCM is solvent, normal-temperature reaction 24h.After reaction terminates, 1M salt pickling is added, aqueous phase is extracted with EA, merge organic phase, concentration Obtain solid 0.429g, yield 72.1%.
2nd, the preparation of hydrocinnamamide yl benzoic acid
The hydrocinnamamide yl benzoic acid ethyl ester 0.8921g (3mmol) for accumulating obtain before is taken, 30ml tetrahydrofurans are dissolved in: Methanol=1:In 1 solution, addition sodium hydrate aqueous solution (0.48g is dissolved in 5ml water) after being completely dissolved, stirring at normal temperature, instead After should terminating, organic phase is evaporated, 1M HCl solutions is added, there is white precipitate generation, is filtered, EA recrystallizations obtain solid 0.65g.Yield 80.46%.
3rd, N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl -4- (3- hydrocinnamoyls amino) benzamides (2) preparation
Take hydrocinnamamide yl benzoic acid 13.7mg (0.05mmol), 18mg (0.05mmol) 3- nitros -4- (2- (thiophenyl) Ethylamino-) benzsulfamide, 1- ethyls -3- (3- dimethylaminopropyls) carbodiimide hydrochloride (EDCI) 19.4mg (0.1mmol), DMAP6.2mg (0.05mmol), is dissolved in anhydrous DCM, normal-temperature reaction 24h, and reaction adds 1M hydrochloric acid solutions, aqueous phase EA after terminating Extraction, merges organic phase, is concentrated to give crude product, crosses Flash posts, obtains sterling 20mg, yield 66.1%.
Embodiment 2-23
Embodiment 1 is repeated, difference is：Using different raw materials, so that compound 1 and 3-15 and 29 in table 1 is made. It is specific as follows：Use phenylacetic acid, 3- phenylacrylic acids, 3- (4- chlorphenyls) acrylic acid, 3- (3- chlorphenyls) acrylic acid, 3- (2- Chlorphenyl) acrylic acid, 3- (4- methoxyphenyls) acrylic acid, 3- (3- methoxyphenyls) acrylic acid, 3- (2- methoxyphenyls) Acrylic acid, 3- (4- trifluoromethyls) acrylic acid, 3- (3- trifluoromethyls) acrylic acid, 3- (2- trifluoromethyls) third Olefin(e) acid, 3- (4- aminomethyl phenyls) acrylic acid, 3- (3- aminomethyl phenyls) acrylic acid, 3- (2- aminomethyl phenyls) acrylic acid and 4- (1- (3, 5,5,8,8- pentamethyls -5,6,7,8- naphthane -2- bases) vinyl) benzoic acid replace embodiment 1 in raw material benzenpropanoic acid, respectively Compound 1,3-15 and 29 is made.
The 3rd step in embodiment 1 is repeated, difference is：Using different raw materials, so that compound 30- in table 1 is made 36.It is specific as follows：Use 4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) benzoic acid, 4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzoic acid and 4- benzoyls benzoic acid are replaced in embodiment 1 3rd step benzene feedstock propionamido- benzoic acid, is made compound 30,33 and 36 respectively；Use the 4- (1- (first of 3,5,5,8,8- five Base -5,6,7,8- naphthane -2- bases) vinyl) benzoic acid replace embodiment 1 in the 3rd step benzene feedstock propionamido- benzoic acid, And 3- nitrobenzene sulfanilamide (SN) and benzene sulfanilamide (SN) replace the 3rd step raw material 3- nitros -4- (2- (thiophenyl) ethylamino-) benzene sulphur in embodiment 1 Acid amides, is made compound 31 and 32 respectively；Use 4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzene first Acid replaces the 3rd step benzene feedstock propionamido- benzoic acid in embodiment 1, and 3- nitrobenzene sulfanilamide (SN) and benzene sulfanilamide (SN) are replaced in embodiment 1 3rd step raw material 3- nitros -4- (2- (thiophenyl) ethylamino-) benzsulfamide, is made compound 34 and 35 respectively.
Embodiment 24
N- (the fluoro- 3- nitrobenzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl The preparation of amine (compound 24 in table 1)：
Synthetic route is：
1st, the preparation of the fluoro- 4- ethyl nitrobenzoates of 2-
Take the fluoro- 4- nitrobenzoic acids (5g, 27.01mmol) of 2- to be dissolved in ethanol, concentrated hydrochloric acid 20 is added into solution and is dripped, is risen Temperature backflow 16 hours, after completion of the reaction, concentration obtain white solid (5.53g, yield：96%).
2nd, the preparation of 4- nitros -2- phenoxy benzoic acid ethyl esters
The fluoro- 4- ethyl nitrobenzoates (1g, 4.69mmol) of 2- are dissolved in diethylene glycol dimethyl ether solution, added thereto Enter phenol (4.41g, 46.90mmol), K2CO3Under the conditions of 100 degree of (1.9g, 14.74mmol), stir 1 hour.After reaction completely, Solution is poured into water, EA extraction, merge organic phase concentration, obtain crude product column chromatography obtain white solid (1.14g, 84.5%).
3rd, the preparation of 4- amidos -2- phenoxy benzoic acid ethyl esters
4- nitro -2- phenoxy benzoic acids ethyl esters (2g, 6.97mmol) are put into 150ml round-bottomed flasks, 30ml is added Ethanol is dissolved, and ammonium chloride (1.9g, 35.52mmol) is dissolved in into 10ml water, is then added in ethanol solution, is warming up to 105 DEG C, treats After solution boiling, iron powder (1.9g, 34.02mmol) is slowly added to, is flowed back one hour.Reaction solution is filtered with diatomite, is evaporated Filtrate, obtains brown solid, and column chromatography obtains white product (1.47g, yield：82.1%).
4th, the preparation of 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) ethyl benzoate
Sequentially added into round-bottomed flask 3- (2- aminomethyl phenyls) acrylic acid (1.39g, 8.55mmol), EDCI (4.47g, 23.31mmol), DMAP (1.14g, 9.32mmol), then adds anhydrous methylene chloride 60ml, after stirring 2 hours at room temperature, to 4- amido -2- phenoxy benzoic acids ethyl esters (2g, 7.77mmol) are added in solution, 15h, terminating reaction, reaction are stirred at room temperature Liquid is washed with 1M hydrochloric acid solution (30ml*3) successively, and organic phase dries concentration, and crude product is separated with anti-phase C18, obtains product white Color solid (1.93g, yield：61.8%).
5th, the preparation of 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoic acid
2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) ethyl benzoate (2g, 4.98mmol) is added Into round-bottomed flask, 10ml methanol and tetrahydrofuran is added, NaOH (1.59g, 39.84mmol) is dissolved in 6ml water, then It is added in above-mentioned solution, stirs 18 hours at room temperature.Reaction solution pH is tuned into faintly acid, ethyl acetate with 1M hydrochloric acid solution Extraction, dries concentration, obtains faint yellow solid (1.74g, 93.6%).
6th, N- (the fluoro- 3- nitrobenzenesulfonylaminos of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) The preparation of benzamide (24)
By 2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoic acid (1g, 2.68mmol) be dissolved in 3ml without In water THF, thionyl chloride (1.59g, 13.39mmol) is added, is stirred at room temperature 8 hours, TLC detection reactions are complete, concentrate, and remove Remaining thionyl chloride.Plus the acyl chlorides that 5ml THF dissolvings are made, the fluoro- 3- nitrobenzene sulfanilamide (SN) of addition 4- (0.65g, 2.95mmol), triethylamine (0.54g, 5.36mmol) is added, is reacted at room temperature 24 hours.After reaction completely, crude product passes through column chromatography Obtain faint yellow solid (0.54g, yield：35.06%).
Embodiment 25-29
Embodiment 24 is repeated, difference is：Using different raw materials, so that compound 23 and 25-28 in table 1 is made. It is specific as follows：Embodiment is replaced using 3- nitrobenzene sulfanilamide (SN), 4- dichlofluanids, 4- chlorobenzenes sulfanilamide (SN), 4- bromobenzenes sulfanilamide (SN) and benzene sulfanilamide (SN) The fluoro- 3- nitrobenzene sulfanilamide (SN) of raw material 4- in 24, is made compound 23 and 25-28 respectively.
Embodiment 30
2- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) ammonia sulphurs Acyl group) phenyl amino) acetic acid (compound 16 in table 1) preparation：
Synthetic route is：
Glycine (63.8mg, 0.85mmol) is dissolved in 3ml DMSO, DIEA (131.8mg, 1.02mmol) is added, plus Enter to be dissolved in 3ml DMSO N- (the fluoro- 3- nitrobenzenesulfonylaminos of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) acryloyls Base amino) benzamide (24) (100mg, 0.17mmol) solution, reacts 6 hours under the conditions of 100 DEG C, terminating reaction, to reaction Appropriate 1M hydrochloric acid solutions are added in liquid, appropriate EA extractions are added, concentration is dried in organic phase washing, and crude product column chromatography obtains yellow and consolidated Body (32mg, yield：30%).
Embodiment 24-36
Embodiment 30 is repeated, difference is：Using different raw materials, so that compound 17-22 in table 1 is made.Specifically It is as follows：Use 3- alanines, 4-Aminobutanoicacid, 5- aminovaleric acids, 6-aminocaprolc acid, 7- aminoheptylic acids and 8- aminocaprylic acid generations For raw material glycine in embodiment 30, compound 17-22 is made respectively.
The chemical constitution of target product is shown in Table 1 in the formula (I) that the present invention is synthesized.Nucleus magnetic hydrogen spectrum and mass spectrometer system are characterized The chemical constitution of target product, its specific data are shown in Table 2.
Target compound structure in the formula of table 1 (I)
The hydrogen spectrum and mass spectrometric data of target compound in the formula of table 2 (I)
Embodiment 37：Bcl-2、Bcl-xLWith the test of Mcl-1 protein affinities
Experimental method：With reference to previous work and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44； ChemMedChem 2011,6,904-21), with gossypol acetate (AT-101) and 4-benzamido-N- (3-nitro-4- (2- (phenylthio) ethylamino) phenylsulfonyl) benzamide (control 1) is as comparison medicine, using fluorescence polarization (FP) method investigates target compound Competitive assays Bcl-2, Bcl-xLWith Mcl-1 albumen with promoting apoptosis protein Bim or Bid The ability that combines of BH3 peptide fragments (fluorescein mark) evaluate its affinity with target protein.Fluorescence polarization signal is by fluorescence point Light photometer is detected under conditions of excitation wavelength 485nm and wavelength of transmitted light are 535nm.By series concentration target compound With fluorescein-labeled Bim or Bid BH3 peptide fragments and Bcl-2, Bcl-xLOr Mcl-1 albumen cultivates 20 points at room temperature together Zhong Hou, detects its fluorescence polarization signal, calculates the IC of the compound50Value.And it is total protein concentration according to used in measurement, glimmering The IC of the total concentration of light polypeptide, the dissociation constant of albumen-polypeptide complex and detection compound50Value, calculates detection compound Reverse transcriptase constant Ki.Experimental result is shown in Table 3, table 4 and table 5.
Sample segment and Bcl-2, Bcl-x in the formula of table 3 (I)LWith Mcl-1 protein affinities
Sample segment and Bcl-2, Bcl-x in the formula of table 4 (I)LWith Mcl-1 protein affinities
Explanation："/" represents not test；IR：Inhibiting rate
Sample segment and Bcl-2, Bcl-x in the formula of table 5 (I)LWith Mcl-1 protein affinities
Explanation："/" represents not test
As a result show, N- substitutions benzenesulfonyl-substituted benzene formyl amine compound of the invention show with Bcl-2, Bcl-xLWith the preferable binding ability of Mcl-1 albumen.Unlisted compound equally shows preferable combination with above albumen Ability.Therefore these compounds, which have, prepares controlling for the disease related to the high expression of Bcl-2 protein families anti-apoptotic members Medicine is treated, antineoplastic is prepared, and prepares synergist and shares to treat tumour with other antineoplastics or radiotherapy Potential use.
Embodiment 38：Anti tumor activity in vitro testing experiment
1st, experimental tumor strain：
This experiment is respectively using tumour cell strain：HL-60 (human leukemia cell), CCRF-CEM (people's acute lymphoblastics Leukaemia), RPMI-8226 (human myeloma cell), U266 (human myeloma cell), SKOV3 (Proliferation of Human Ovarian Cell), MCF-7 (human breast cancer cell), A375 (human melanoma cell) and NCI-H23 (human lung carcinoma cell) are (purchased from the medical work in Shanghai Industry research institute).
2nd, sample preparation：
After being dissolved with DMSO (Merck), solution or uniform suspension that PBS (-) is made into 1000 μ g/mL are added, then With PBS (-) dilution containing DMSO.Positive control drug is AT-101, ABT-737 and 4-benzamido-N- that Abbott develops (3-nitro-4- (2- (phenylthio) ethylamino) phenylsulfonyl) benzamide (control 1).
3rd, test method：
According to experiment detection and pertinent literature (Bioorg Med Chem Lett 2012,22,39-44； Nature.2005,437,677-681), using mtt assay.It is 4~5 × 10 that 96 orifice plates, which add concentration per hole,4Individual/mL cell hangs The μ L of liquid 100, put 37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ L/ holes, if duplicate hole, 37 DEG C, 5%CO2Make Use 72h.Lysate is added after the 5mg/mL μ L of MTT solution 20, effect 4h are added per hole, 100 μ L/ holes are put in incubator, dissolving Afterwards 570nm OD values are surveyed with the full-automatic ELIASAs of MK-2.Anti tumor activity in vitro is shown in Table 6.
In-vitro multiplication inhibitory action of the sample segment to human body tumour cell in the formula of table 6 (I)
Explanation："/" represents not test
As known from Table 6, N- of the invention replaces benzenesulfonyl-substituted benzene formyl amine compound to human blood tumour and reality Body knurl shows that the inhibiting tumour cells activity of preferable broad-spectrum anti-tumor activity, particularly part of compounds is better than ABT-737, It is better than or suitable with AT-101, unlisted compound also shows that preferable broad-spectrum anti-tumor activity.It imply that the present invention Compound be expected have good DEVELOPMENT PROSPECT.
To sum up, replace benzenesulfonyl-substituted benzene formyl amine compound the invention provides a class N-, resist with good Tumor promotion, with preferable DEVELOPMENT PROSPECT.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art Member, on the premise of the inventive method is not departed from, can also make some improvement and supplement, and these are improved and supplement also should be regarded as Protection scope of the present invention.

Claims (9)

1. a class N- replaces benzenesulfonyl-substituted benzene formyl amine compound, it is characterised in that its general structure such as formula (I) institute Show：
In formula,
R1Group is-ZR5(II), wherein, Z is
R5It is hydrogen atom, unsubstituted or substituted aromatic monocyclic, unsubstituted or substituted hydrogenated aromatic condensed ring, unsubstituted or substituted fragrance Condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Straight chain, side chain or cyclic alkane base, halogen；
Or R5Group is-YR6(III), wherein, Y is C1~C7Straight chain, side chain or cyclic alkane base, C1~C7Straight chain, side chain or ring Shape alkylene, R6It is hydrogen atom, unsubstituted or substituted aromatic monocyclic, wherein, substituent is monosubstituted or polysubstituted, is halogen, Unsubstituted or halo C1~C5Straight chain, side chain or cyclic alkane base, C1~C5Alkoxy grp, nitro, trifluoromethyl, cyano group, sulfonic acid Base, carboxyl；
Or R5Group is-YR6(III), wherein, Y is unsubstituted or substituted aromatic monocyclic, and substituent is monosubstituted or polysubstituted, R6 Group is VR10(VII), wherein, V isR10To be unsubstituted or Substituted aroma condensed ring, substituent is monosubstituted or polysubstituted, is C1~C5Straight chain, side chain or cyclic alkane base, halogen,
R2The position of substitution is located at two or three-digit, is hydrogen atom, hydroxyl, amino, halogen, C1~C5Straight chain, side chain or cyclic alkane Base；
Or R2Group is-XR7(IV), wherein, X is O, N, S,R7It is hydrogen atom, aromatic monocyclic, fragrance Condensed ring, C1~C7Straight chain, side chain or cyclic alkane base,
R3Group is hydrogen atom, halogen, amino, hydroxyl, C1~C5Straight chain, side chain or cyclic alkane base；
Or R3Group is-NWR8(V), wherein, W is C1~C10Straight chain, side chain or cyclic alkane base, C1~C10Straight chain, side chain or Cyclic olefin base, R8It is hydrogen atom, sulfonic group, carboxyl, nitro, trifluoromethyl, cyano group；
Or R8Group is-UR9(VI), U is S, O, N,R9It is hydrogen atom, aromatic monocyclic, aromatic condensed ring, C1~C7Straight chain, side chain or cyclic alkane base,
R4The position of substitution is located at two or three-digit, is hydrogen atom, nitro, trifluoromethyl, cyano group, sulfonic group, carboxyl, C1~C5Straight chain Or branched alkane alkyl, halogen, hydroxyl, amino.
2. N- according to claim 1 replaces benzenesulfonyl-substituted benzene formyl amine compound, it is characterised in that
R1Group is-ZR5(II), Z isR5Group is-YR6(III), wherein, Y It is C1~C7Linear paraffin base, C1~C7Linear alkene base, R6It is unsubstituted or substituted aromatic monocyclic, wherein, substituent is singly to take In generation, be halogen, unsubstituted C1~C5Linear paraffin base, C1~C5Alkoxy grp, trifluoromethyl,
R2For hydrogen atom, or R2Group is-XR7(IV), wherein, X is O, N, S, R7It is aromatic monocyclic,
R3Group is hydrogen atom, halogen；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is carboxyl, sulfonic group；
Or R8Group is-UR9(VI), U is S, O, N, R9It is aromatic monocyclic,
R4For hydrogen atom, nitro.
3. N- according to claim 1 replaces benzenesulfonyl-substituted benzene formyl amine compound, it is characterised in that
R1Group is-ZR5(II), wherein, Z isR5It is not Substituted aroma is monocyclic, unsubstituted or substituted aromatic condensed ring, wherein, substituent is monosubstituted or polysubstituted, is C1~C5Linear paraffin Base,
R2For hydrogen atom,
R3Group is hydrogen atom；
Or R3Group is-NWR8(V), wherein, W is C1~C10Linear paraffin base, R8Group is-UR9(VI), U is S, O, N, R9It is Aromatic monocyclic,
R4For hydrogen atom, nitro.
4. N- according to claim 1 replaces benzenesulfonyl-substituted benzene formyl amine compound, it is characterised in that described N- substitution benzenesulfonyl-substituted benzene formyl amine compound be following compounds in any one：
1) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (2- phenylacetyl groups amino) benzamide
2) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- hydrocinnamoyls amino) benzamide
3) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (phenyl) Acryloyl amino) benzoyl Amine
4) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- chlorphenyls) Acryloyl amino) benzene Formamide
5) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- chlorphenyls) Acryloyl amino) benzene Formamide
6) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- chlorphenyls) Acryloyl amino) benzene Formamide
7) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- methoxyphenyls) acryloyl group ammonia Base) benzamide
8) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- methoxyphenyls) acryloyl group ammonia Base) benzamide
9) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- methoxyphenyls) acryloyl group ammonia Base) benzamide
10) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- trifluoromethyls) acryloyl groups Amino) benzamide
11) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- trifluoromethyls) acryloyl groups Amino) benzamide
12) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- trifluoromethyls) acryloyl groups Amino) benzamide
13) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (4- aminomethyl phenyls) Acryloyl amino) Benzamide
14) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (3- aminomethyl phenyls) Acryloyl amino) Benzamide
15) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3- (2- aminomethyl phenyls) Acryloyl amino) Benzamide
16) 2- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) acetic acid
17) 3- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) propionic acid
18) 4- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) butyric acid
19) 5- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) valeric acid
20) 6- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) caproic acid
21) 7- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) enanthic acid
22) 8- (2- nitros -4- (N- (2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl) sulfonamides Base) phenyl amino) octanoic acid
23) N- (3- nitrobenzenesulfonyls) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
24) N- (the fluoro- 3- nitrobenzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzoyl Amine
25) N- (the fluoro- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
26) N- (the chloro- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
27) N- (the bromo- benzenesulfonyls of 4-) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
28) N- (benzenesulfonyl) -2- phenoxy groups -4- (3- (2- aminomethyl phenyls) Acryloyl amino) benzamide
29) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (4- (1- (3,5,5,8,8- pentamethyl -5,6, 7,8- naphthane -2- bases) vinyl) benzoyl-amido) benzamide
30) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (1- (3,5,5,8,8- pentamethyl -5,6,7, 8- naphthane -2- bases) vinyl) benzamide
31) N- (3- nitrobenzenesulfonyls) -4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) Benzamide
32) N- (benzenesulfonyl) -4- (1- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- bases) vinyl) benzoyl Amine
33) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (3,5,5,8,8- pentamethyls -5,6,7,8- four Hydrogen naphthalene -2- carbonyls) benzamide
34) N- (3- nitrobenzenesulfonyls) -4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzamide
35) N- (benzenesulfonyl) -4- (3,5,5,8,8- pentamethyl -5,6,7,8- naphthane -2- carbonyls) benzamide
36) N- (3- nitros -4- (2- (thiophenyl) ethylamino) benzenesulfonyl) -4- (benzoyl) benzamide.
5. the crystal formation, pharmaceutically acceptable of N- substitution benzenesulfonyl-substituted benzene formyl amine compounds described in claim 1 Inorganic acid salt or acylate, hydrate, solvate or prodrug.
6. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition contains pharmaceutically acceptable excipient or load Body, and described in claim 1 N- substitution benzenesulfonyl-substituted benzene formyl amine compound or claim 6 described in N- Replace the crystal formation, pharmaceutically acceptable inorganic acid salt or acylate, hydration of benzenesulfonyl-substituted benzene formyl amine compound Thing, solvate or prodrug.
7. N- substitution benzenesulfonyl-substituted benzene formyl amine compounds described in claim 1, or the N- described in claim 6 Replace the crystal formation, pharmaceutically acceptable inorganic acid salt or acylate, hydration of benzenesulfonyl-substituted benzene formyl amine compound The purposes of thing, solvate or prodrug in medicine is prepared, it is characterised in that described medicine is used for：
A) treatment and Bcl-2, Bcl-xLThe disease or symptom related to Mcl-1 activity；
B) it is antitumor；Or
C) as antineoplastic or the synergist of radiotherapy.
8. purposes according to claim 8, it is characterised in that described tumour is leukaemia, myeloma, oophoroma, breast Gland cancer, melanoma or lung cancer.
9. the N- described in claim 1 replaces the preparation method of benzenesulfonyl-substituted benzene formyl amine compound, its feature exists In comprising the following steps：
Intermediate (VIII) and 2- or 3- substitution -4- substituted benzenes sulfanilamide (SN) (Ⅸ), generate target compound under the conditions of condensation reaction (Ⅰ)；
Wherein, intermediate (VIII) structural formula is：
2- or 3- substitutions -4- substituted benzenes sulfanilamide (SN) (Ⅸ) structural formula is：
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